Ormaplatin resistance is associated with decreased accumulation of its platinum (II) analogue, dichloro(D,L-trans)1,2-diaminocyclohexaneplatinum (II)

Abstract

Summary Ormaplatin (also known as tetraplatin) is a platinum-containing analogue which has recently undergone clinical trials. Ormaplatin may undergo conversion to dichloro(D,L-trans)-1,2-diaminocyclohexaneplatinum(II) [PtCl2(trans-dach)]. The cisplatin-resistant murine lymphoma cell lines E8 and E5, were found to be cross-resistant to ormaplatin and PtCl2(trans-dach). We found an inverse rank correlation between drug resistance and drug accumulation for PtCl2(trans-dach) similar to our previous findings with cisplatin; however, accumulation of ormaplatin in the resistant cells was increased. Ormaplatin cytotoxicity appears to result primarily from extracellular conversion to PtCl2(trans-dach), since ormaplatin cytotoxicity was decreased under conditions where extracellular conversion to PtCl2(trans-dach) was minimised. Co-incubation with different inhibitors of energy metabolism resulted in a 65-70% increase in PtCl2(trans-dach) accumulation in the parental cell line Ri.1 and a 113-307% increase in the resistant cell line E5 which suggests that the decrease in accumulation in E5 may be at least partly energy dependent. We conclude from these findings that crossresistance to ormaplatin is associated with an energy-dependent decreased accumulation of PtCl2(trans-dach) in these cisplatin-resistant cell lines.

Effect of thiols exported by cancer cells on the stability and growth-inhibitory activity of Pt(IV) complexes

“…The reduction of ormaplatin in cell culture medium by extracellular thiols appears to be the only example where extracellular thiols have been recognized as important factors by biotransformations of platinum complexes. Comparing the extracellular thiol concentrations found in cell cultures of R1.1 (1.4 0.3 lM) and E5 (2.1 0.8 lM) (Rischin and Ling 1996) with our data shows that the levels of thiols in the medium of four dierent cancer cell lines are in the same order of magnitude after a 1-h incubation (Table 3). In addition, our results indicated that cancer cells continue to export thiols during their rapid growth phase, reaching a maximal 20-fold increase by 72 h. The identity of these thiols is not yet known but it is anticipated that glutathione makes up a signi®cant portion.…”

“…Rischin and Ling (1996) showed that a cisplatinsensitive mouse T cell lymphoma cell line R1.1 and a cisplatin-insensitive cell line E5 release thiols into the cell culture medium and that the stability of ormaplatin is decreased as a result. The reduction of ormaplatin in cell culture medium by extracellular thiols appears to be the only example where extracellular thiols have been recognized as important factors by biotransformations of platinum complexes.…”

“…ND not determined Extracellular thiol concentration (lM)Rischin and Ling 1996. Thiol content of phosphate-buered saline after 1 h incubation on the 2nd day after plating the cells and removing the conditioned culture medium…”

Current Status of Novel Multifunctional Targeted Pt(IV) Compounds and Their Reductive Release Properties

“…Its ability to overcome cisplatin resistance is attributed to the asymmetric nature of DNA damage, which evades recognition by DNA repair proteins [ 63 ]. Furthermore, iproplatin and ormaplatin, both demonstrating superior clinical oncological activity, serve as promising indicators for the development of novel tetravalent platinum-based drugs [ 4 , 64 , 65 , 66 ]. Researchers are also exploring the binding of other biologically active ligands using axially positioned tetravalent platinum groups, such as halogen, hydroxyl, and carboxyl.…”

Development of Novel Pt(IV)-Carbohydrate Derivatives as Targeted Anticancer Agents against Osteosarcoma

“…These complexes are referred to as pro-drugs as they must be reduced from the inactive Pt(IV) complex to their active Pt(II) species by the reducing environment within cancer cells, which leads to a more targeted approach of drug delivery to the cancer cells [ 4 ]. The most promising Pt(IV) drugs are satraplatin [ 5 , 6 ], ormaplatin [ 7 , 8 ] and iproplatin [ 9 , 10 ] but, despite promising results, none to date have been approved for widespread use in cancer treatments ( Figure 1 a) [ 3 ]. Promising strategies for imparting selectivity to Pt(IV) pro-drugs is the use of tumour-targeting ligands.…”